Whole-Brain Radiation Therapy With or Without Lapatinib Ditosylate in Treating Patients With Brain Metastasis From HER2-Positive Breast Cancer
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Purpose
This randomized phase II trial studies how well whole-brain radiation therapy (WBRT) with or without lapatinib ditosylate works in treating patients with brain metastasis from HER2-positive breast cancer. Radiation therapy uses high energy x rays to kill tumor cells. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy together with lapatinib ditosylate is an effective treatment for brain metastasis from breast cancer
| Condition | Intervention | Phase |
|---|---|---|
|
HER2-positive Breast Cancer Male Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer Tumors Metastatic to Brain |
Drug: lapatinib ditosylate Radiation: whole-brain radiation therapy |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase II Randomized Study of Whole Brain Radiotherapy in Combination With Concurrent Lapatinib in Patients With Brain Metastasis From HER2-Positive Breast Cancer: A Collaborative Study of RTOG and KROG |
- CR rate in the brain measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on MRI scan of the brain [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
- CR rate in the brain measured using revise RECIST version 1.1 based on MRI scan of the brain [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
- Objective response rate (ORR) (CR + PR) measured using RECIST version 1.1 based on MRI scan of the brain [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
- Lesion-specific ORR (CR + PR) [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
- Overall response (CR, PR, or stable disease [SD]) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
- Treatment-related toxicity as measured by Common Terminology Criterial for Adverse Events (CTCAE) version 4 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
- CNS PFS [ Time Frame: From the time of randomization to the date of first failure (CNS progression or death due to any cause), assessed up to 2 years ] [ Designated as safety issue: No ]Estimated by the Kaplan-Meier method. Compared between arms using the log rank test.
- Progression-free survival [ Time Frame: From the date of randomization to the date of first failure or last follow-up, assessed up to 2 years ] [ Designated as safety issue: No ]Estimated by the Kaplan-Meier method. Compared between arms using the log rank test.
- OS [ Time Frame: From the date of randomization to the date of first failure, assessed up to 2 years ] [ Designated as safety issue: No ]Estimated by the Kaplan-Meier method.
| Estimated Enrollment: | 143 |
| Study Start Date: | September 2012 |
| Estimated Primary Completion Date: | July 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Arm I (WBRT)
Patients undergo WBRT QD 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.
|
Radiation: whole-brain radiation therapy
Undergo WBRT
Other Names:
|
|
Experimental: Arm II (lapatinib ditosylate, WBRT)
Patients receive lapatinib ditosylate PO QD on days 1-42 and undergo WBRT as in arm I in the absence of disease progression or unacceptable toxicity
|
Drug: lapatinib ditosylate
Given PO
Other Names:
Radiation: whole-brain radiation therapy
Undergo WBRT
Other Names:
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To determine if there is a signal for an increase in complete response (CR) rate in the brain at 12 weeks post whole-brain radiotherapy (WBRT) as determined by magnetic-resonance imaging (MRI) scan of the brain, with the addition of lapatinib ditosylate (lapatinib) to WBRT compared to WBRT alone.
SECONDARY OBJECTIVES:
I. To evaluate CR rate in the brain at 4 weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT compared to WBRT alone.
II. To evaluate objective response rate in the brain at 4 and 12 weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT compared to WBRT alone.
III. To evaluate lesion-specific objective response rate (CR + partial response [PR]) at 4 and 12 weeks post WBRT.
IV. To evaluate overall response with addition of lapatinib to WBRT compared to WBRT alone.
V. To evaluate the central nervous system (CNS) progression-free survival (PFS) rate and overall survival (OS) rate, with the addition of lapatinib to WBRT compared to WBRT alone.
VI. To evaluate treatment-related adverse events when adding lapatinib to WBRT compared to WBRT alone.
OUTLINE: This is a multicenter study. Patients are stratified according to graded prognostic assessment for breast cancer (II vs III vs IV), use of concurrent trastuzumab (yes vs no), use of non-CNS-penetrating HER2 blockade at time of study entry (none vs trastuzumab ± pertuzumab), and history of stereotactic radiosurgery (SRS) for limited brain metastasis (no vs yes). Patients are randomized to 1 of 2 treatment arms.
Arm I: Patients undergo whole-brain radiation therapy (WBRT) once daily (QD) 5 days a week for 3 weeks in the absence of disease progression or unacceptable toxicity.
Arm II: Patients receive lapatinib ditosylate orally (PO) QD on days 1-42 and undergo WBRT as in arm I in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 and 12 weeks and then every 12 weeks thereafter.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Pathologically (histologically or cytologically) proven diagnosis of invasive breast cancer
- Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer (3+ staining by immunohistochemistry or HER2 gene amplification by fluorescent in situ hybridization[FISH] or silver in situ hybridization [SISH] ≥ 2.2)
Brain metastases that fulfill 1 of the following:
- Progressive parenchymal brain metastases following stereotactic radiosurgery for 1-3 brain metastases, with at least 1 new measurable lesion
- Progressive parenchymal brain metastases following surgical resection of 1-3 brain metastases, as long as at least 1 brain metastasis is measurable
- At least 1 measurable, unirradiated parenchymal brain lesion (≥ 10 mm on T1-weighted gadolinium-enhanced MRI) within 21 days prior to study entry
- No leptomeningeal disease
- Karnofsky performance status ≥ 60%
- Able to swallow and retain oral medication (Note: for patients unable to swallow tablets, an oral suspension preparation is acceptable)
- Absolute neutrophil count (ANC) ≥ 1,200 cells/mm³
- Platelets ≥ 70,000 cells/mm³
- Hemoglobin [Hgb] ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable)
- Creatinine < 1.5 times institutional upper limit of normal (ULN)
- Bilirubin < 1.5 times institutional ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 times institutional ULN with or without liver metastasis
- Women of childbearing potential must have a negative serum pregnancy test within 21 days prior to study entry
- Sexually active women of childbearing potential and sexually active men must practice adequate contraception during therapy and for 12 months after protocol treatment completion
- Women should not breastfeed while on this study
- No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- No prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
No severe, active co-morbidity, defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- Transmural myocardial infarction within the last 6 months
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of study entry
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; hepatic or biliary disease that is acute or currently active or that requires antiviral therapy (with the exception of patients with Gilbert syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)
- History of left ventricular ejection fraction (LVEF) below institutional normal unless repeated and within institutional normal range within 90 days of study entry
- No grade 2 or greater rash of any cause at time of study entry
- No grade 2 or greater diarrhea of any cause at time of study entry
- At least 14 days between FINAL dose of prior chemotherapy and study entry, with recovery of toxicities to grade 0 or 1
- No prior whole-brain radiation therapy (WBRT)
- No prior lapatinib therapy
- No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields except patients who have progressed following stereotactic radiosurgery for 1-3 brain metastases, with at least one new lesion
- No concurrent intensity-modulated radiation therapy
Contacts and Locations
Show 68 Study Locations| Principal Investigator: | In Ah Kim | Radiation Therapy Oncology Group |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01622868 History of Changes |
| Other Study ID Numbers: | NCI-2012-01977, RTOG-1119, U10CA021661, CDR0000735353 |
| Study First Received: | June 15, 2012 |
| Last Updated: | March 6, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Breast Neoplasms Neoplasm Metastasis Breast Neoplasms, Male Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Neoplastic Processes |
Pathologic Processes Lapatinib Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses |
ClinicalTrials.gov processed this record on May 16, 2013